Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.

Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas United States of America

Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas United States of America; Centro de Pesquisas Rene Rachou FIOCRUZ Belo Horizonte Minas Gerais Brazil

Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas United States of America; Department of Pediatrics and Human Genome Sequencing Center Baylor College of Medicine Houston Texas United States of America; Texas Children's Hospital Houston Texas United States of America

Department of Pediatric Neurology DNA Laboratory 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics and Adolescent Medicine Division of Pediatric Neurology University Medical Center Göttingen Georg August University Göttingen Germany

Nemours Biomedical Research Alfred 1 duPont Hospital for Children Wilmington Delaware United States of America

Nemours Biomedical Research Alfred 1 duPont Hospital for Children Wilmington Delaware United States of America; Jefferson Medical College Thomas Jefferson University Philadelphia Pennsylvania United States of America

Nemours Biomedical Research Alfred 1 duPont Hospital for Children Wilmington Delaware United States of America; Jefferson Medical College Thomas Jefferson University Philadelphia Pennsylvania United States of America; University of Delaware Department of Biological Sciences Newark Delaware United States of America

University of Rochester Medical Center Rochester New York United States of America

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Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants